Design of selective peptidomimetic agonists for the human orphan receptor BRS-3

Dirk Weber, Claudia Berger, Peter Eickelmann, Jochen Antel, Horst Kessler

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44 Scopus citations


New tool substances may help to unravel the physiological role of the human orphan receptor BRS-3 and its possible use as a drug target for the treatment of obesity and cancer. In continuation of our work on BRS-3, the solid- and solution-phase synthesis of a library of low molecular weight peptidomimetic agonists based on the recently developed short peptide agonist 4 is described. Functional potencies of the compounds were determined measuring calcium mobilization in a fluorometric imaging plate reader (FLIPR) assay. Focusing on the N-terminus, the D-Phe-Gln moiety of 4 was modified in a combinatorial SAR-oriented medicinal chemistry approach. With the incorporation of N-arylated glycine and alanine building blocks azaglycine, piperazine, or piperidine and the synthesis of semicarbazides and semicarbazones, a number of highly potent and selective compounds with a reduced number of peptide bonds were obtained, which also should have enhanced metabolic stability.

Original languageEnglish
Pages (from-to)1918-1930
Number of pages13
JournalJournal of Medicinal Chemistry
Issue number10
StatePublished - 8 May 2003


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